In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. A083-A083
Abstract:
Background: MLN0128 is an oral inhibitor of mTOR kinase and mTORC1/2 signaling. Alisertib is an oral inhibitor of Aurora A kinase. Senescence and upregulation of genes in the PI3K/AKT/mTor pathway have been observed in triple-negative breast cancer (TNBC) patient-derived xenograft models treated with alisertib, with greater tumor growth inhibition demonstrated in combination with MLN0128 as compared to each agent alone. An investigator-initiated trial was developed to evaluate the combination of MLN0128 and alisertib in patients with advanced solid tumors, followed by an expansion cohort in metastatic TNBC and other selected cancers. The goals of this ongoing study are to evaluate safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of the combination. Results of dose escalation are presented here. Methods: Patients with advanced solid tumors refractory to standard therapy were treated orally at escalating doses with the combination of MLN0128 daily on a continuous schedule and alisertib twice daily (BID) on days 1-7 of a 21-day cycle. Dose escalation was conducted according to a standard 3+3 design. Key eligibility criteria included HgbA1c & lt;7%, fasting serum glucose & lt;130mg/dL and fasting triglycerides & lt;300mg/dL, normal cardiac function, no condition with potential to cause excessive daytime sleepiness (including chronic hypoxia) and no risk of malabsorption of oral medications. PK assessments were performed at various time points after single-agent and combination dosing. Results: A total of 16 patients with refractory cancers were enrolled in dose escalation. No dose-limiting toxicity (DLT) was observed in dose level 1 (MLN0128 1mg/alisertib 30mg) or dose level 2 (2mg/30mg). At the third dose level (2mg/40mg) 2 of 7 patients experienced a DLT (grade 3 fatigue/confusion and grade 2 GERD/nausea leading to study discontinuation). In an alternate dose level cohort evaluating MLN0128 3mg and alisertib 30mg, 2 of 2 patients experienced a DLT of grade 3 fatigue. The maximum tolerated dose (MTD) of the combination was determined to be MLN0128 2mg daily and alisertib 30mg BID. Most common adverse events (AEs) of any grade included alopecia, diarrhea, fatigue and rash in 19% each and nausea in 31% of patients. Most common Grade 3 AEs included fatigue (19%) and decreased neutrophil count (31%). Dose modification was required in 56% of patients, most often due to neutropenia. Median time on study was 3 cycles (range 1-15) at data cutoff. Best response of stable disease was observed in 5 patients (31%), with prolonged stable disease noted in a patient with ER+/HER2- breast cancer (15 cycles) and a patient with castrate-resistant prostate cancer (10 cycles). PK assessments indicate no significant drug interaction between agents. Cmax was 24.7 (± 13.6) ng/mL for MLN0128 and 1049 (±363) ng/mL for alisertib at combination MTD doses. MLN0128 AUC was 128.2 (±72.7) ng/mLxhr and alisertib AUC0-8 was 6119 (±2331) ng/mlxhr at these doses. Conclusions: MLN0128 2mg daily on a continuous schedule and alisertib 30mg BID days 1-7 of a 21-day cycle is the MTD of the drug combination. An expansion cohort in patients with TNBC and other selected cancers is currently enrolling at this dose. Functional imaging and serial tumor biopsies are being integrated into this cohort to assess the pharmacodynamic interactions of the combination. Citation Format: S. Lindsey Davis, Elaine T. Lam, Bradley R. Corr, Cindy L. O'Bryant, Ashley Glode, Nichole Adler, Todd M. Pitts, John J. Tentler, Anna Capasso, Kyrie Dailey, Natalie J. Serkova, Colin D. Weekes, Daniel L. Gustafson, Christopher H. Lieu, Wells A. Messersmith, Stephen Leong, S. Gail Eckhardt, Jennifer R. Diamond. A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A083.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-17-A083
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2062135-8
SSG:
12
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